Chemical compounds



Patented July 23, 1946 2,404,691 CHEMICAL ooMPon ns Walter G. Christiansen, Glen Ridge, and Sidney E. Harris, Nutley, N. J. & Sons, New York, N.

York

No Drawing. Continuation of application Serial No. 163,034, September 9,

, assignors to E, R. Squibb Y., a corporation of New 1937. This applica;

tion August 30, 1944, Serial No. 552,013

6 Claims. (Cl. 260-473) This application is a continuation of Christiansen and Harris application Serial No. 163,034, filed September 9, 1937.

This invention relates to, and has for its object the provision of, certain amino-alcohol esters of oxy-benzoic acids, acid-addition salts thereof, and methods of preparing them. The esters of this invention are comprehended by the general forwherein X is a halogen, and Y, R', and R"" have the above-noted signification, is reacted with an alcohol comprehended by the general formula HO-eR-e-N wherein R, R, and R'f have the above-designated meaning, to produce the desired ester, However, other methods hereinafter described may be employed to produce the compounds of the present invention.

The amino-esters of this invention are generally recovered in the form of their additionsalts with hydrochloric acid. However, other acids forming addition-salts with amines may be used in place of hydrochloric; such acids are boric, nitric, lactic, tartaric, citric, phosphoric, sulfuric, picric, and picrolonic. The additionsalts may be converted into the free bases in the usual manner.

benzene is distilled off 2 The following examples are illustrative of the invention.

EXM PLE p-diethylamina-ethyl ester of p-ethcryebcneoic acid 10 g. .of p-ethcxy-benze l chlor d fli w fl in 5.0 cc. of dry benzen s reated th 6-8 o fl=diethylamino- $h 1; a eci tate qrma a d e reaction is om stee b hea in on t ter bath. Aft r CQQllIl the el amy ri Off the precipitate and treat ng t with a s t cess of 2N pfitassium hydroxide solution, the ester is extracted with ether and dried with anhydrous sodium sulfate. On passing dry hydrogen chloride throu h the ether solution, a crystalline precipitate of the nycr ehlgride 9f the ester forms; it is filtered 01f, washed with dry ether, and then meltsat 172 5-1735? C. (corrected).

EX P E 2 p-[N-ethyl-N- (n-amyU-dminol :ethyl ester .of p,- ethoscyrbenzoic .acid

41 pf e h yrhe z r chl rid .qi elv q n 5 c of dry b nzene ramm d $9 3.0 minu e with a solution comprising 3.5 g. of p.- [ii-ethyln-amyl .-.am nolfil anel in 9 (42- o d b nzene; distilling oil the benzene in .vacuq, dissolv-' s the resid e (c ud h dr ch oride p he sired e er) in a oho .decohrizin with earb and ne recipitatin with d ether. f l pwe b v l zation fr m an meme- P t ole e her) mixt re. yi l he hy rochloride of the es ed p oduct havin a m in o t of C, (corrected).

4.6 g. of p-ethoxyebenaoyl chloridedissolved in 12 cc. .of dry benzene is admixed with a solution comprising 4.35 g. .of fi-[di-(n-butyD-aminolethanol in 5 cc. of dry benzene, the reaction proceeding to completion at room temperature; the under reduced pressure; t n rec y ta izin th crude h droch or e of t desi ed este .i Qm wan etrole ether) mixture yields a product having'a melting point of 1445-1455 C. (corrected).

EXAMPLE 4 Gamma-[di- (n-butyl) aminol-propyl ester of pethomy-belnzoic acid A solution c0mprising 4.6g. of p-ethoxy-benzoyl chloride in 12 cc. of dry benzene is added to 4.7 g.

a product melting at about 85.6-86.6 C, (corrected) EXAMPLE 5 c-diethylamino-ethyl ester of p-n-butozty-beneoic acid I A solution of 10.5 g. of p-n-butokybenzoyl chloride in 25 cc. of dry benzene is refluxed for two hours with a solution comprising 6.191 g. of ,B-diethylamino-ethanol in cc. of, dry benzene; the

solution is allowed to cool, and 'thehydrochloride of the desired ester separates as a heavycrystalline deposit; after filtering and washing the precipitate with benzene and dry ether, a compound having a melting pointof 146 C. (corrected) is obtained. i EXAMPLE 6 ,c-dimethylamino-ethyl ester 0f p-n biLtoficy benzoic acid {1.5 g. of ,c dim'ethylamino-ethanol dissolvedin 10 cc. of dry benzene is treated with a solution comprising 10.5 g. of p-n-but'oXy-benzo'yl chloride in cc. of dry benzene; filtering off the precipitate and washing it with benzene and petroleum ether yields the hydrochloride of the'desired ester, having a melting point of 132-133": C.

EXAMPLE 7 e-diejthylamino ethyl ester of 2- ethoay g 3- methyl-beneoic acid 11.5 g. 'of 2 ethoxy-3-methyl-benzoyl chloride dissolved in 50 cc. of dry benzene is treated with a solution comprising 13 g. of ,B-diethylaminoethanol in cc. of. dry benzene; as the reaction proceeds, a crystalline deposit separates out; filtering and washing the precipitate, evaporating the filtrate and washings to dryness, redissolving the residue in alcoholic hydrochloric acid, followed by reprecipitation therefrom with dry ,ether, yields the desired product, havinga melting point of 97-97.5 C.

The 2-ethoxy-3-methyl-benzoy1 chloride may 'be prepared by treating 3.5 g. of sodium dissolved in 100 cc. of absolute alcohol with 25 g. of ethyl o-cresotinate, after which 20 g. of ethyl bromide is added and the solution is boileduntil neutral to moist litmus; then after filtering, and distilling the alcohol from the filtrate, the ethyl ether of ethyl o-cresotinate, having a boiling point'of 116-118 'C./6 mm., is fractionated in vacuo from the residue; dissolving 21 g. of this fraction in alcoholic sodium hydroxide, cooling, and acidifying the solution with hydrochloric acid, yields 2-ethoxy-B-methyl-benzoic acid as an oily precipitate, which may be extracted with ether and subsequently dried; this extract, after distilling off the ether, is boiled for two hours with 20 g. of thionyl chloride, whereupon fractional distillation yields the desired intermediate, 2-ethoxy-3-methyl-benzoyl chloride, which passes 'over at 1021Q5 C./2.5 mm.

EXAMPLE 8 s-dz'ethylamino-ethyl .ester of o-ethoxy-benzoic 7 hydrochloride in benzene, the hydrochloride of the ester sparating out; then filtering, and purifying the filter cake by reprecipitation from its alcoholic solution with dry ether, yields a product having a melting point of 139139.5 C. (corrected).

EXAMPLE 9 p-dzethylamino-ethyl ester of p-(p-diethylammoethowy) -benzoic acid 5 g. of p-diethylaminoethoXy-benzoyl chloride suspended in a solution comprising 2 g. of p-diethylamino-ethanol in 20 cc. of dry benzene is refluxed for several hours; the precipitate (mono-hydrochloride of the ester), after filtration and purification by reprecipitating the filter cake from a mixture of alcohol and ether,

yields the desired product as a very hygroscopic substance,

The p-(B-diethylamino-ethoxy) -benzoic chloride may be prepared as follows: 13 g. methyl ester of p-hydroxy benzoic acid is, dissolved in 35 cc. acetone, and 15 g. anhydrous potassium carbonate is suspended therein. The mixture is refluxed andxstirred, and 13 g. ,B-diethylamino: ethyl chloride is added, the reaction mixture being heated andstirred for 15 hours. The inorganic salts precipitated are filtered off, andthe filtrate concentrated by distillation; the residue is treated with an excess of aqueous sodium hydroxide, and boiled until saponification is complete. Any alkali-insoluble material is removed by extracting with a solvent such as ether or benzene; the clear alkaline solution is acidified with HCl, evaporated to dryness in vacuo, and the residue extracted with absolute alcohol. The extract is filtered, evaporated to dryness, and the residue recrystallized from methyl alcohol and ether. The hydrochloride of p-(p-diethylaminoethoxy) -benzoic acid obtained is in the form of white needles, melting at -161 C. (corrected).

19.5 g. p-(,B-diethylamino-ethoxy) -benzoic acid and 15 g. phosphorus pentachloride are heated together on the steam bath until reaction ceases. The P0013 which forms is distilled off in vacuo, and the residue is allowed to crystallize; crystallization may be hastened by triturating with acetone and filtering. V l

The hydrochloride of p-(c-diethylaminoethoxy) -benzoy1 chloride formed melts at 143 C. (corrected) EXAMPLE 10 V p-diethylamino-ethyl ester of 2-methyl-4-ethoxybenzoic acid tion of 6 g. of this fraction in 20 cc. of dry benzene is treated with 7.6 g. of ,B-diethyl-amino-ethanol dissolved in 10 cc. of dry benzene, and crystals of diethylamino ethanol hydrochloride separate out; filtering off the precipitate, treating the filtrate with alcoholic hydrochloric acid, and diluting it with dry ether, yields the hydrochloride of the desired ester as a white crystalline solid melting at 101-103" C.

EXAMPLE 11 v,6-diethylamina-ethyl ester of 3-methyZ-4-ethomy-beneoic acid 13 g. of 3-methyl-4-ethoxy-benzoic acidandjlfa g, of phosphorus pentachloride are heated on a steam .bath .f or 30 minutes, and then ,hactionally distilled in vacuo, the firaction.3 =-;methyl-4-ethoxy-benzoyl chloride being 0btained as acolorless liquid .boiling at 14fl'152 (EL/6 mm. Asolution comprising 6.5 g. of this fraction dissolved in ,16 cc. of dry benzene, is mixed with 7,5 g. .ofdiethylamino-ethanol dissolvedin 18 0.0..of ,dry benzene, and the mixture boiled for 60minutes; coolins t rea i n m x u e causes a white crystalline precipitate of fl-diethylarnino-ethanol hydrochloride to separate out completely; then filtering, treating the filtrate with alcoholic hydrochloric .acid, and distillinaofi the benzene an ohol, leaves a white. o id res due wh ch u on re rysta ation .irom amixture of abso ute alc hol anddry ether, yields the ydrochloride cf the d sired product as ,a white c ys allin ;-pr e .pitat having a meltin nointeof "142;,5-14 51C.

EXAMPLE l2 G'amma-diethylamino-propyl ester of p-ethoatybenzoicacid 5.5 g. of gamma-diethylamino-propanol, 9.3 g. of p-ethoxy-benzoyl chloride, and 25cc. ofsodium hydroxide (10% solution) are vigorously stirred for-30 minutes; the mixture is cooled, the oily layer extracted with benzene, and the resultant solution is washed with dilute sodium hydroxide and water; distilling off the benzene, dissolving the residual oil in absolute alcoholic hydrochloric acid solution, and diluting the latter with ether, causes the hydrochloride of the desired ester to separate out as a crystalline precipitate, "which, after filtering and recrystallizing from an alcoholether mixture, yields the desired product, having a melting point of 148.5-1495" C. i

E AMPLE 13 Z-(diethylamz'no)ecyclohezcyl ester of memory-- benzoic acid A solution comprising 6.8 g. of 2- diethylaminocyclohexanol-l dissolved in 75 cc. of dry benzene is treated With 10 g. of finelypowdered anhydrous potassium carbonate suspended therein; 7.3 E .of p-ethoxy-benzoyl chloride is added to the mixture and the latter is refluxed, With stirring, for several hours, whereupon 100 cc, of water and 100 cc. of benzene are added thereto and the diluted solution is shaken vigorously; and. the benzene layer containing the desired tester separates out. Decanting offthe benzene solution, washing it with dilutesodium hydroxide and Water, distilling off the benzene, and adding an alcoholic solution of hydrochlorioacid to'the residue, followed by dilution with dry ether, yields the crude hydrochleride o t es ed Lest ras' n .q l p e i te which rapidly crystallizes ;.11ltfering and purifying the filter cake by recrystallizingjrom an alcoholether mixture, yieldsthe desired product, melting at 184-185" c.

EX M 1&

c-hydrory-gamma-diethyZamin0-propyl ester 07 p-ethoacy-benzoic acid' hydrochloric acid is added to the filtrate, the reultant solution being evaporated to dryness, :Re-

crystallizin the residue trom alcohol and dry ether, yields the desiredproduct, which is a mixture of two isomers and has a meltin -p range of -126 C.

Exelvmt n v15 6- NeethyleNl- (p-hydroxythyl) .-.aminol ethyl ester of p-ethozryebeneoiciaetd 6.73. .of 8,19adihydroxy triethylamineis dissolved in 100 cc, oidrybenzene; L4 g, of potassium carbonate is suspended therein, and after adding 9.2 g. of p-.ethoxy-benz0yl chloride, the reactants are refluxed, with stirring, for two'hours. iFilteringfthe reactants, evaporating thehenzene, and distilling the residue in vacuo yields the desired product as a thick, colorless ,oil, soluble in dilute acids, and having a boiling point of 2I8+f225 C.'/8

mm, Its hydrochloride is very hygroscopic.

EXAMPLE 16 ,a-di- (N -dimethylaminomethyl:) -n-propyl ester of p-ethoay e'nzoic acid ExA RLn l7 e-dz'ethylamino-z'sohexyl ester of p-ethocwbens i eoic acid =1 g. of p diethylamino-isohexanol, 6,1 g. of p-ethoxy-benzoyl chloride, 10 got potassium car- .bonataand 50 cc. of dry benzene are reacted in the manner described in Example .15. The ester formed boils at 1757-" C./2.5 mm. and 193-195 c./5 mm.

Ex-AMPnE 18 cmmaw i tiwlamico- (debt/dre sy) er ors/1 ester of ,p-n-butoay benzoic acid A solution of 5 g. of I-diethylamino-ZB-propanediol, 6.2 g. of p-n-butoxy-benzoyl chloride, and 10 g. of potassium carbonate, in 50cc. of benzene, is refluxed for 90 minutes and treated in accordance with Example 14. The desired product, being a mixturepf two isom rs, has no sharp melting point (79-96" 0.).

EXAMPLE 19 This com'poundis obtained inthe same manner as that of Example '15, except that p-n-butoxybenzoyl chloride is used instead of the p-ethoxybenzoyl chloride, and the amount of the ethyl diethanolamine used is 7 g. Thedesiredproduct has, a boiling point of 216-220 C./3 mm. Its hydrochloride is hygroscopic. i

EXAMPLE .20

0;,0t-tli- (N -dzmethylaminomethyl-) -n-propyl ester of p-n butozcy-be'nzoic acid This compound is prepared in the same manner as that of Example 16, except that p-n-butoxybenzoic acid is used instead of th p-ethoxy benzoic acid. The desired substance has a melting point of lllfC; l a 1 7 -Ex AMrLE 21 B-diethyldminoethgl ester of m-ethoxy-benzoic acid 11.5 g. of m-ethoxy-benzoyl chloride dissolved in 50 cc. of dry benzeneis mixed with 14.5 g. of diethylamino-ethanol dissolved in 50 cc. of benzene, and. the mixture is heated on a steam bath for 60 minutes, whereupon the precipitate formed (diethylamino-ethanol hydrochloride) is filtered off and 'the benzene is distilled from the filtrate, yielding a residue which after purification by vacuum distillation has a boiling point of 163-175 C./ 2 Diss'olving this product in alcoholic hydrochloric acid. and reprecipitatin with ether, yields the hydrochloride of the ester melting at EXAMPLE 22 e-diethylamz'no-ethyl 'ester' of p- (,B-ethowy-ethoxw-Denzoic acid 15 g. of methyl p-hydroxy-benzoate and 18 g. of fl-bromo-ethyl ether dissolved in50 cc. of. dry acetone, are treated with a suspension therein of 20 g. of powdered .anhydrous potassium carbonate, and the mixture is then refluxed, with stirring, for 15 hours. The potassium carbonate and potassium bromide precipitated are filtered oh, the acetone is distilled from the filtrate, and the residue boiled with dilute sodium hydroxide solution until dissolved; p-(p-ethoxyethoxy)-benzoic acid is precipitated with hydrogenchloride, and after filtering, washing, drying the precipitate, and recrystallizing from benzene, yields a product melting at 131-132 C. Heating a mixture comprising 6 g. of this benzoic acid derivative and 6 g. of phosphorus pentachloride to'about 70 C. until hydrogen chlorid is no longer evolved, and fractionally distilling in vacuo, yields p-(fl-ethoxyethoxy) -benz'oyl chloride as a colorless oil having a boiling point of 150 160 C./ mm. Refluxing a mixture comprising 5 g. of this benzoyl chloride derivative, 5.1 g. of diethylamino-ethanol, and 50 cc. of dry benzene, for 30 minutes, filtering off the precipitate (diethylamino ethanol hydrochloride), evaporating ofi the benzene and alcohol, treating the residue with ether, and adding alcoholic hydrogen chloride, yields the desired ester as .a vwhite'crystalline hydrochloride melting at 102-1035 C. EXAMPLE 23 fi-dz'ethylamino-ethyl ester of p-n-propoa'y-benzoic acid After mixing and refluxing solutions comprising 9.5g. of p-n-propoxy-benzoyl chloride and 11.2 g. of diethylamino-ethanol, each dissolved in 25 cc. of benzene, for 30 minutes, the reaction mixture is cooled, and 100 cc. of dilute sodium hydroxide solutionis added; then after vigorously shaking the mixture, the benzene layer, contain" ing the desired ester, separates and is decanted off. Then Washing the benzene solution with water, distilling off the benzene, and vacuumdistilling the residue, yields the desired ester, having a boiling point of 160-165" C. /4 mm.

The hydrochloride is obtained, in accordance with Example 21, in the form of a white crystalline solid, melting at 135-l36 C.

EXAMPLE 24 -e-dietiiylamino-ethyl1 ester ofp-isopropoxy-benbenzoyl chloride and 7.7 g. 01 diethylamino e thanol, each in 25 cc. of dry benzene, are mixed and warmed on a steam bath for 60 minutes. Filtering off the precipitateddiethylamino-ethanol hydrochloride, and evaporating the benzene from the residue, the'latter is treated with ether and alcoholic hydrochloric acid to yield the'desired ester as thehydrochloride in the form of a white crystalline solid meltin'gat 125.5 C. 1

' 1 EXAMPLE 25 I p-dicthylcmir oeethyl ester of p-allyloivy-berlzo'ic This compound is'prepared in the same manneras that of Example 24, except that 8 g. of p-alloxy-benzoyl chloride (instead of the -npropoxy derivative) and 9.5 g. of diethyl-aminoethanol are'used. Theboiling point of the ester is 165-175 C./4 mm. The hydrochloride melts at 130 0.

EXAMPLE 26 fl-diethyldmino-ethylj ester 0] -(p-phenyaeth cry) -benzoic acid The aracyl halide for the preparation of this compound is obtained as follows: To 15.2 g. of methyl p-hydroxy-benzoate dissolved in a solution of 2.5 g. of metallic sodium incc. of abso-. lute alcohoL-isadded 20.5 g. of B-phenyl-ethyl bromide, andthe mixture is refluxed? hours. Filtering off the inorganic salts, distilling ofi the alcohol fromthe filtrate, hydrolyzing the residue by boiling it with aqueous alkali, precipitating the free'acid with hydrogen chloride, filtering, washing, and drying, .yields the intermediate, p- (18-phenyl-eth0xy)benz0ic acid, in the form of a white powder, melting at 163-164" C. Dissolving 10 g. of this intermediate compound in 40 cc. of phosphorus oxychloride, adding 8.6 g. of phosphorus pentachloride, warming themixture on a steam bath, evaporating off the excess phosphorus oxychloride, adding 8.6 g. of phosphorus pentachloride, warming the mixture on a steam bath, evaporating'off the excess phosphorus oxychloride, andvacuum-distilling the residue, yields the acid chloride of the intermediate, having a boiling point (with slight decomposition) of 215-230 C./5 mm., f

EXAMPLE 27 p-diethyZamino-cthyl ester of p-(fi-brornallyloxy) -benzoic acid solution comprising 17 g. methyl p-hydroxyacid, melting at 200C. (with decomposition).

Warming 9.5 g. of this benzoic acid derivative with 7.7 g. of phosphorus pentachloride, and fractionating the mixture in vacuo, yields thedesired acid chloride intermediate, boiling at c./5 mm.

Refiuxing a mixture comprising 6 g. of this p-(p-bromalloxy)-benzoy1 chloride and5.1 g. of

'diethylamino-ethanol, each dissolved in 25 cc. of

dry benzene, for half an hour, filtering off the precipitate and treating the filtrate with alcoholic hydrochloric acid, yieldsaiter evaporating the benzene and hydrogen chloride and recrystalliz- 9. ing the residue from alcohol and ether, the desired compound, melting at 81.5-83.5 C.

EXAMPLE 28 fi-dz'ethylamino-ethyl ester of 3-methomy-4- ethoxy-benzoic acid 9.3 g. of 3-methoxy-4-ethoxy-benzoic acid'reacted with 10.5 g. of phosphoru pentachloride, yields the acid chloride, boiling at 147-150" .C./5 mm. and having a melting point of 72" C. Treating 9 g. of this 3-methoxy-4-ethoxy-benzoy1 chloride and 9.8 g. of. diethylamino-ethanol in accordance-with Example 27, yields the desired compound as a white crystalline powder having a; melting-point 0i 1715-1725 C.

EXAMPLE 29 Delta-dicthylamino-delta Jmtenyl ester of pethory-benzoic acid 2.5 g. of p-ethoxy-benz'oate of brombutenol is mixed with 5.5 g. ofdiethylamine and 15 cc.

of benzene; the mixture isheated' in a sealed tube at 125-135 C; for about 8 hours; after cooling, the contents of the tube is treated with water; the water-insoluble product is then separated or extracted with ether; the ether extract, after washingwith water, is driediover anhydrous sodium sulphate; the ether,fr'ee diethylamine,- and benzene are removed by distillation of the extract; the oily residue is subjected to further heating on a steam bath under diminished pressure, therebyremovingthe solvent by distillation; the product is dissolved in" a small amount of alcoholic hydrochloric acid, and precipitated as an oily hydrochloride by the addition of ether; the supernatant alcohol-ether mixture is decanted off, leaving an oily residue which, after extraction with dry ether, yields the desired productasa yellowish white crystalline substance melting at 146-147 C. l

The intermediate p-ethoxy-benzoate of brombutenol may bepreparedias fOllOWSZ' 51-5 g.of dry sodium p-ethoxy benzoat'e is mixed With 8 g. of a-gamma-dibrombuteiie and g. of dry xylene; the mixture is-heated in a sealed tube at. 165-17.0 C. for about. 6 hours, the, contents offthe tube'is then extracted with dilute alcohol and ether; theether extract, after washing with water; is dried over anhydrous sodium sulphate;-

the ether and xylene; are removed by distillation of the extract on a steambath under diminished pressure; the oily residue is fractionated in. a high vacuum; the first fraction coming over at 95-97"C./;3'-4' mm.; the second at 165-175 C./3

,mml; the third at 200 C./3 mm.; thesecond fraction being the desired intermediate, pethoxy-benzoate of brombutenol, 7

'EXAMPLE 30 :amino-ethyl. ester of p-ethory-benzoic acid potassium bromide and potassium carbonate filtered oh, and the filtrate treated with a solution of hydrogen chloride in. ether. The reddish- ;brown semi-solid which separates out crystallizes,

and. is filtered off, washed-with ether, and. dried in a vacuum over; calcium. chloride; The ex-- Av mixture: comprising 9.95 g: 'of' phenacyl bromide, 4.4 g. ethylaminoethanoL. and cc.

10 tremely hygroscopic substance formed is N- phenacy-N-ethyhamino-ethanol hydrochloride.

A mixture comprisingg'k28-g. of N-phenacyl- N-ethyl-amino-ethanol; 7.5 g. p-ethoxy-benzoyl chloride, 30 cc. benzene,-and 8 g. potassium carbonate is "stirred and refluxed for five hours, filtered, and the filtrate is treated with a-solution of hydrogen chloride in ether. The impure material is then purifiedby crystallization from a chloroiorm- (petroleum ether) mixture. The white crystalline substance obtained is" the N- phenacyl-N-ethylamino ethyl? ester of p-ethoxybenzoic acid (hydrochloride).

0.9 g. ofthis hydrochlorideis dissolved in 60 cc. alcohol containing 0.3.gsplatinum oxide. The mixture is shaken .ror eight. hours. under. a. pressure-oi- 35 pounds of hydrogen; it. is then filtered, and-thefiltrate is-concentrated to. a smallvolume and diluted with ether. .The brownish-white Ex-steers 31 as'-di (dimethyldmino) isopropyl ester of 15-- propoxy-bensoie acid (hydrochloride) 2 g. pp -di- (dimethylamine) isopropanol and 3.2 g. p-n-propoxy benzoylchloride are each dis- Solved in 5'00; chloroform; and the solutions are mixed. A precipitate forms, which-is dissolved by adding dry acetoneyand-thereactioniscompleted by warming for a short time on the water bath. The solvents are then distilled oh, and the residue recrystallized from" a mixture of alcohol and ether-. The product, which. melts at 203 C. witlrdecomposition, is a mixture of the monoand di-hydrochlorides. I

EXAMPIZE 32' s-diethylamino-ethyl' ester of p-(p'-am-ino-benzyloxy) benzoic acid (mono-hydrochloride) 5 g. B-diethylamino-ethyl. ester of p- (pi-nitroben zyloxy) -benzoic ,.acid hydrochloride is dissolvedin absolute alcohol and shakenwith hydrogen gas in the presence of Adams platinum oxide catalyst (Org! Sync, Col. Vol. page 452), until no more hydrogen is absorbed; The catalyst is then removed by filtration", and? dry ether is added'to precipitate the hydrochloride; on recrystallizing by-dissolv-ing in absolute alcohol and adding dry ether, a product melting at -187 C. (corrected) is obtained.

EXAMPLE 33.

imethyZ-gamma-diethyZamino-propyl ester of peethory benaoicucid (hydrochloride) prcduct is-dissolvedin absolute "alcohol and precipitatedby addingdryether. The hydrochloride is thus obtained as-a White crystalline solid melting-at 122-124 C. (corrected). 1

EXAMPLE 34 I Gammc-dimethylamino-pr0pyl esterlofatonethyl- 4n-but0ry.-benzoicacid 1.53 g. gamma-dimethylamino-propanol and 3117 g. 3-methyl 4'-n-butoxy-benzoyl chloride are dissolved in 10'cci of dry alcoholefre'e chloroform.

The solution is warmed on a steam bath for half an hour and the product precipitated as the hydrochloride by adding dry ether; it may be purified by r'edissolving in chloroform or absolute alcohol a'nd reprecipitating. The product i s'a white crystalline powder melting" at 125.5-125.5 (corrected). I

r ExAMr-Ln35 (Ld' di (dimethylaminomethyl) gamma-phenyl-n- Znropyl ester of 3-methyl-4-n-butozry-benzoic acid (hydrochloride) 36 g. of the ethyl ester of 3-methyl-4-hvdroxybenzoic acid and27.4 g. of n-butyl'bromide dissolvedjn 200 cc. acetone, are treated with- 84 g. anhydrous potassium carbonate in themanner described in Example 22. The product, ,3-methyl -nebutoxy-benzoic acid, is recrystallized from 60% alcohol in the form of'white plates melting at 144-146? C. (corrected). 1 a

15 g. of this acid is reacted with 15 g. phosphorus pentachloride in the manner described in Ex The product, 3-methyl-4-n-butoxy- EXAMPLE 36 Gamma-dimethyZamino-n-propyl ester of p-(ephenyZ-ethoxy) -benzoic acid (hydrochloride) 1.55 g. gamma-dimethylamino-propanol and 4.0 g. p-(p-phenylethoxy) -benzoyl chloride are reacted in chloroform in the manner indicated in Example 35. The product melts at 156.5-15'7.5 C. (corrected).

' EXAMPLE 37 a-methyl-a-dimethyZaminOmethg Z-n-amyl ester of 3-methyZ-4-n-butory-benzoic acid (hydrochloride) 4.4 g. of 3-methyl-4-n-butoxy-benzoyl chloride and 3.0 g. of a-methyl-a-dimethylaminomethyln-amyl alcohol are reacted together in 10 cc. of chloroform as directed in Example 35. The product melts at 126-131 C. (corrected).

EXAMPLE, '38

e-diethylamz'no-ethyl ester of p-(p'mitro-benzyloxy)-benzoic acid (hydrochloride) 5.5 g. p-nitro-benzyl bromide is added to a solution or 6.4 g. p-diethylamino-ethyl ester of p-hydroxy-benzoic acid in 50 cc. dry acetone in which g. anhydrous potassium carbonate is suspended. The mixture is refluxed for 12 hours, filtered. and'the acetone distilled from the filtrate. The residue is treated with a solution of hydrogen chloride in alcohol, some acetone is added, then ether; and the product precipitates as the hydrochloride. It is purified by recrystallization from acetone and ether, and melts at 145-146 C. (corrected) The following are among the many other compounds embraced by the present invention, and may be prepared according to the directions given above:

39. at di(dimethylaminomethyl) -amy1 ester of p-(p-phenyl-ethoxy) -benzoic acid.

40. p-(N-piperidino)-ethyl ester of p-ethoxy benzoic acid. Q I

41. Delta-diamylamino-n-butyl ester of 2-propoxy-3-methy1-benzoic acid.

42. or-methyl-a-dimethylaminomethyl-gammaphenyl-n-propyl ester of p-(p-phenyl-ethoxwbenzoic acid.

43. a methyl-a-dimethylaminomethyl-gammaphenyl-n-propyl ester of 3-methyl-4-n butoxybenzoic acid. I V

44. Gamma-diethylamino-n-propy1 esterof 3- ethyl-4-n-propoxy-benz'oic acid., V j H 45. Gamma-dimethylainino-n-propyl ester of 3-methyl-4- (,B-phenyl-ethoxy) -benzoic acid. v

46. a methyl-a-dimethylaminomethyl-namyl ester of 3-methyl-4-(p-phenyl-ethoxy)-benzoic acid.

47. a-methyl-u-dimethylaminomethyl-gammaphenyl-n-propyl ester of ethoxy) -benzoic acid.

48. a methyl-u-dimethylaminomethyl-n-amyl ester of p-(p-phenyl-ethoxy) -benzoic acid. 5

49. ,4 di(dimethylaminomethyl) gammaphenyl-n-propyl ester of 3-methyl-4-(p-pheny1- ethoxy)-benzoic acid." r

50. a,a-di (dimethylaminomethyl) -n-amylester of 3-methyl-4-(p-phenyl-ethoxy) -benzoic acid.

51. a,a-di dimethylaminomethyl-n-amyl ester of 3-methyl-4-n-butoxy-benzoic acid. 1

52. Delta diethylamino n butyl ester' of 3- methyl-4-n-butoxy-benzoic acid. g

53. ,3 [N ethyl N09 phenyl-ethyl) -amino] ethyl ester of p-ethoxy-benzoic acid. a

54. on methyl 13 benzyl gamma dimethylamino-propyl ester of p-ethoxy-benzoic acid.

55. a benzyl oz diethylaminomethyl propyl ester of p-n-butoxy-benzoic acid.

56. a-methyl oz diethylaminomethyl-n-butyl ester of p-n-propoxy-benzoic acid.

57. p-diethylamino-ethyl ester of 2-methyl-4- I propoxy-benzoic acid.

58. ,8 dimethylamino n propyl I ester of 3- methyl-4-propoxy-benzoic acid.

59. B-(,e-diethylamino-ethoxy) -ethyl ester of p-ethoxy-benzoic acid. i; EXAMPLE 60 The intermediate, 3-methyl-4-( s-phenyl-ethoxy)-ben zoyl.chloride used in the preparation ,of the compounds of Examples 45, .46, 47, 49, and

50 may be prepared as follows: 23 g. of the ethyl ester of 3- methyl-4-hydroxybenzoic acid, 3.2g. of sodium, and 23 g. of phenyl-ethyl bromide are reacted together in 200 cc. absolute alcohol in the manner described in Example 26. The product, 3-methyl-4(flphenyl-ethoxw-benzoic acid, melts at -152 C. (corrected). 1 i

13 g. of this acid, reacted with 10.5 g. phosphorus pentachloride in the manner described in Example 26, gives the corresponding acid chloride boiling at 210-215 0. at 1.0 mm. P .1

The invention may be variously otherwise embodied, within the scope of the appended claims.

We claim: 1. A compound of the group consisting of: amino esters of the general formula.

. I wherein R represents a divalent alkyl residue with 2 to 3 carbon atoms, and each of R and R" represents an alkyl residue with 2 to 4 carbon atoms; and'acid-addition salts thereof.

13 14 2. An acid-addition salt of an amino ester of 4. An acid-addition salt of p-diethylaminothe general formula ethyl p-ethoxy-benzoate.

h 5. The hydrochloride of p-diethylamino-ethyl p-ethoxy-benzoate. 5 6. The hydrochloride of 5 [di (n butyl) aminoJ-ethyl p-ethoxy-benzoate. wherein each of R and R." represents an alkyl I residue with 2 to 4 carbon atoms. WALTER G. CHRISTIANSEN.

3. ,B-diethylamino-ethyl ester of p-ethoxy- SIDNEY E. HARRIS.

benzoic acid. 10 

